Targeted Delivery of Small Interfering RNA (siRNA) Against Oncogenes by using pH-Sensitive Nanoparticles to Inhibit Breast Cancer Cells Proliferation and Survival

Harnessing siRNA technology has promising results in limiting the proliferation and survival of cancer cells by ‘silencing’ the expression of targeted genes. Carbonate apatite nanoparticle system has been employed to electrostatically complex with the siRNAs in order to prevent their degradation and renal clearance, and enhance the uptake by target cells following intravenous administration. This study would have significant impact in validating the potential applications of pH-sensitive carbonate apatite nanoparticles for delivery of siRNA cocktails in different models of breast cancer as well as in clinical trials

Development of MicroRNAs as Potential Therapeutics against Cancer

MicroRNAs (miRNAs) are small noncoding RNAs that function at the posttranscriptional level in the cellular regulation process. miRNA expression exerts vital effects on cell growth such as cell proliferation and survival. In cancers, miRNAs have been shown to initiate carcinogenesis, where overexpression of oncogenic miRNAs (oncomiRs) or reduced expression of tumor suppressor miRNAs has been reported. In this review, we discuss the involvement of miRNAs in tumorigenesis, the role of synthetic miRNAs as either mimics or antagomirs to overcome cancer growth, miRNA delivery, and approaches to enhance their therapeutic potentials

Carbonate apatite nanoparticles carry siRNA(S) targeting growth factor receptor genes egfr1 and erbb2 to regress mouse breast tumor

Cancer cells lose their control on cell cycle by numerous genetic and epigenetic alterations. In a tumor, these cells highly express growth factor receptors (GFRs), eliciting growth, and cell division. Among the GFRs, epidermal growth factor receptor-1 (EGFR1) (Her1/ERBB1) and epidermal growth factor receptor-2 (EGFR2) (Her2/ERBB2) from epidermal growth factor (EGF) family and insulin-like growth factor-1 receptor (IGF1R) are highly expressed on breast cancer cells, thus contributing to the aggressive growth and invasiveness, have been focused in this study. Moreover, overexpression of these receptors is related to suppression of cell death and conferring resistance against the classical drugs used to treat cancer nowadays. Therefore, silencing of these GFRs-encoding genes by using selective small interfering RNAs (siRNAs) could be a powerful approach to treat breast cancer. The inorganic pH sensitive carbonate apatite nanoparticles (NPs) were used as a nano-carrier to deliver siRNA(s) against single or multiple GFR genes in breast cancer cells as well as in a mouse model of breast carcinoma. Silencing of egfr1 and erbb2 simultaneously led to a reduction in cell viability with an increase in cell death signal in the cancer cells and regression of tumor growth in vivo

siRNAs targeting growth factor receptor and anti-apoptotic genes synergistically kill breast cancer cells through inhibition of MAPK and PI-3 kinase pathways

Breast cancer, the second leading cause of female deaths worldwide, is usually treated with cytotoxic drugs, accompanied by adverse side-effects, development of chemoresistance and relapse of disease condition. Survival and proliferation of the cancer cells are greatly empowered by over-expression or over-activation of growth factor receptors and anti-apoptotic factors. Identification of these key players that cross-talk to each other, and subsequently, knockdown with their respective siRNAs in a synchronous manner could be a promising approach to precisely treat the cancer. Since siRNAs demonstrate limited cell permeability and unfavorable pharmacokinetic behaviors, pH-sensitive nanoparticles of carbonate apatite were employed to efficiently carry the siRNAs in vitro and in vivo. By delivering selective siRNAs against the mRNA transcripts of the growth factor receptors, such as ER, ERBB2 (HER2), EGFR and IGFR, and anti-apoptotic protein, such as BCL2 in human (MCF-7 and MDA-MB-231) and murine (4T1) breast cancer cell lines, we found that ESR1 along with BCL-2, or with ERBB2 and EGFR critically contributes to the growth/survival of the cancer cells by activating the MAPK and PI-3 kinase pathways. Furthermore, intravenous delivery of the selected siRNAs aiming to suppress the expression of ER/BCL2 and ER/ERBB2/EGFR groups of proteins led to a significant retardation in tumor growth in a 4T1-induced syngeneic mouse model

Oncogenic Signaling in Tumorigenesis and Applications of siRNA Nanotherapeutics in Breast Cancer

Overexpression of oncogenes and cross-talks of the oncoproteins-regulated signaling cascades with other intracellular pathways in breast cancer could lead to massive abnormal signaling with the consequence of tumorigenesis. The ability to identify the genes having vital roles in cancer development would give a promising therapeutics strategy in combating the disease. Genetic manipulations through siRNAs targeting the complementary sequence of the oncogenic mRNA in breast cancer is one of the promising approaches that can be harnessed to develop more efficient treatments for breast cancer. In this review, we highlighted the effects of major signaling pathways stimulated by oncogene products on breast tumorigenesis and discussed the potential therapeutic strategies for targeted delivery of siRNAs with nanoparticles in suppressing the stimulated signaling pathways

Carbonate apatite nanoparticles carry siRNA(s) targeting growth factor receptor genes <i>egfr1</i> and <i>erbb2</i> to regress mouse breast tumor

<p>Cancer cells lose their control on cell cycle by numerous genetic and epigenetic alterations. In a tumor, these cells highly express growth factor receptors (GFRs), eliciting growth, and cell division. Among the GFRs, epidermal growth factor receptor-1 (EGFR1) (Her1/ERBB1) and epidermal growth factor receptor-2 (EGFR2) (Her2/ERBB2) from epidermal growth factor (EGF) family and insulin-like growth factor-1 receptor (IGF1R) are highly expressed on breast cancer cells, thus contributing to the aggressive growth and invasiveness, have been focused in this study. Moreover, overexpression of these receptors is related to suppression of cell death and conferring resistance against the classical drugs used to treat cancer nowadays. Therefore, silencing of these GFRs-encoding genes by using selective small interfering RNAs (siRNAs) could be a powerful approach to treat breast cancer. The inorganic pH sensitive carbonate apatite nanoparticles (NPs) were used as a nano-carrier to deliver siRNA(s) against single or multiple <i>GFR</i> genes in breast cancer cells as well as in a mouse model of breast carcinoma. Silencing of <i>egfr1</i> and <i>erbb2</i> simultaneously led to a reduction in cell viability with an increase in cell death signal in the cancer cells and regression of tumor growth <i>in vivo</i>.</p